Title

Protein homeostasis gene dysregulation in pretangle-bearing nucleus basalis neurons during the progression of Alzheimer's disease

Document Type

Article

Abstract

Conformational phosphorylation and cleavage events drive the tau protein from a soluble, monomeric state to a relatively insoluble, polymeric state that precipitates the formation of neurofibrillary tangles (NFTs) in projection neurons in Alzheimer's disease (AD), including the magnocellular perikarya located in the nucleus basalis of Meynert (NBM) complex of the basal forebrain. Whether these structural changes in the tau protein are associated with pathogenic changes at the molecular and cellular level remains undetermined during the onset of AD. Here, we examined alterations in gene expression within individual NBM neurons immunostained for pS422, an early tau phosphorylation event, or dual labeled for pS422 and TauC3, a later stage tau neoepitope, from tissue obtained postmortem from subjects who died with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild/moderate AD. Specifically, pS422-positive pretangles displayed an upregulation of select gene transcripts subserving protein quality control. On the other hand, late-stage TauC3-positive NFTs exhibited upregulation of messenger RNAs involved in protein degradation but also cell survival. Taken together, these results suggest that molecular pathways regulating protein homeostasis are altered during the evolution of NFT pathology in the NBM. These changes likely contribute to the disruption of protein turnover and neuronal survival of these vulnerable NBM neurons during the progression of AD.

Keywords

Alzheimer's disease, Cholinergic basal forebrain, Mild cognitive impairment, Protein homeostasis, Tau

Publication Date

6-1-2016

Publication Title

Neurobiology of Aging

ISSN

01974580

E-ISSN

15581497

Volume

42

First Page

80

Last Page

90

PubMed ID

27143424

Digital Object Identifier (DOI)

10.1016/j.neurobiolaging.2016.02.031

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